Closure-cap and container as a two-chamber cartridge for nebulisers for producing aerosols and active substance formulations, suitable for storage

ABSTRACT

The invention relates to an apparatus comprising a closure-cap and a container in the form of a two-chamber cartridge in which an active ingredient and a solvent can be stored separately until the apparatus is used in a nebuliser, as well as an active substance concentrate in which the active substance is present as a solution or suspension for storage purposes.

The present invention relates to an apparatus comprising a closure-capand a container in the form of a two-chamber cartridge in which anactive ingredient and a solvent can be stored separately until theapparatus is used in a nebuliser, and to a propellant-free activesubstance concentrate in which the active ingredient is present inhighly-concentrated form for storage purposes. The cartridge accordingto the invention serves especially as a container for medicamentformulations for use in nebulisers for production of aerosols forinhalative or nasal application, especially for use in propellant-freenebulisers.

In the International Patent Application WO91/14468 “Atomising Device andMethods” and also in WO 97/12687, cf FIGS. 6a and 6B and the associateddescription, an apparatus for the propellant-free administration of ametered quantity of a fluid medicament for inhalative application isdescribed. In such a nebuliser, a medicament solution is converted bymeans of high pressure into a lung-accessible aerosol and sprayed. Forthis kind of application, it can be necessary to decant the solutionswhich contain the active ingredients into containers so that only asmall amount of air and gas residue is included. Containers which aresuitable for this purpose, are, for example, disclosed in InternationalPatent Application PCT/EP95/03183, to which express reference will bemade for the purposes of the present invention. The containers describedthere are above all suitable for those medicaments which can be storedover a longer period of time in the form of an aqueous or ethanolicsolution.

In order to increase the shelf-life of active ingredients in solutionwhich break down after only a few months, DE 196 15 422 discloses acartridge which has two chambers for the separate storage of the solventand an active ingredient in the form of a powder or a compressed tablet.The cartridge is designed in such a way that when the cartridge isinserted in apparatus for the production of the aerosol (inhaler), thechamber which contains the active ingredient is penetrated by a canulain the inhaler, so that the active ingredient comes into contact withthe solvent in the container and is dissolved. Although this cartridgefor storing inhalation formulations in the aforementioned containers hasmany advantages, from time to time the canula of the inhaler, asspecified, can become blocked when it penetrates the chamber whichcontains the active ingredient. For this reason, no medicamentsuspensions can be stored in the aforementioned chamber. Furthermore, itcan not always be guaranteed that active ingredients formulated as asolid will dissolve sufficiently rapidly in the solvent, so that thedesired active ingredient concentration can only be achieved with a timedelay. In this way, trouble-free use of the inhaler charged with thecartridge is made difficult.

The present invention solves the aforementioned problems and also thoseknown from the prior art in that a new two or multi-chamber cartridge(container) is provided where two or more components of the inhalationformulation can be stored separately from one another.

In particular, the invention relates to an apparatus comprising aclosure-cap and a container which can be used as a cartridge (container)for nebulisers. In the cartridge, at least one active ingredient and onesolvent of a therapeutic formulation specified for inhalative or nasalapplication can be stored separately until the cartridge is installed inthe nebuliser as specified. As nebulisers, high-pressure atomisers andespecially the high-pressure atomisers from WO91/14468 and WO 97/12687,FIGS. 6a and 6b and the associated description, are particularlysuitable. Here, the cartridge is shaped so that the separately-storedcomponents can be mixed together during use of the cartridge in theinhaler without causing a blockage of the canula, so that the medicamentpreparation is formed, ready for use, within the shortest possible time,preferably within a few minutes and possibly within a few seconds. Inthe context of the present invention, it is unimportant whether themedicament formulation which is to be applied is a solution or asuspension; what is critical is that the formulation which is to beapplied is a fluid formulation which can be converted by means of anebuliser of the aforementioned type into an aerosol for inhalative ornasal application. For administration by inhaling using the inhalerdescribed hereinbefore, however, formulations in the form of solutionsare generally preferred to those in the form of suspensions.

Within the scope of this description, the expressions nebuliser,atomiser, inhaler and high-pressure atomiser, and also metering aerosoland aerosol are used as synonyms unless otherwise stated.

DESCRIPTION OF THE INVENTION

The present invention is constructed in a similar manner to theinvention in the aforementioned document DE 196 15 422, to the entiretyof which reference will expressly be made. As in DE 196 15 422, thecartridge according to the invention has at least two possible ways ofstoring formulations or ingredients of formulations: the container ofthe cartridge and another chamber which is preferably formed in theclosure-cap of the cartridge. Some ingredients of the formulation to beadministered are stored in the chamber until ready for use, while theremaining ingredients are stored in the container, including themajority of the liquid component. This liquid component contains thesolvent or suspension agent, or the majority thereof, provided foradministration, preferably a solvent, and optionally other componentswhich will be specifically described more fully hereinafter. By the term“majority thereof” is meant that part of the formulation to be appliedthat is not already formulated together with the active substance in thechamber. In the following text, no great distinction is drawn betweensolvent and mixture of solvents, i.e. the term “solvent” includes amixture of solvents, unless otherwise stated. Conversely, however, amixture of solvents always comprises at least two fluid,chemically-different components.

Active substances can be stored in a pharmaceutically-stable manner inthe abovementioned chamber over a fairly long period of time of, forexample, several months or possibly years, especially active ingredientswhich cannot be stored in a pharmaceutically stable manner in ethanolicsolutions over the aforementioned time span.

The chamber is preferably formed in the closure-cap; however, it may belocated elsewhere in the cartridge, e.g. in the interior of thecontainer.

For reasons of clarity, in the course of this description the expression“chamber” is used for both a single chamber and also for a plurality ofchambers of the same type located directly adjacent to one another,unless otherwise specified.

The chamber has at least one but preferably two openings. Theclosure-cap is designed so that the contents of the chambers can betransferred into the interior of the chamber through the one openingwhich is present in every case by means of an external influence, evenwhen the closure-cap seals the container tightly. This opening ishereinafter referred to as the inner opening.

In addition, the chamber can optionally have a further opening. In thecartridge's closed condition, a connection between the chamber and theexternal environment can be made by means of this opening, so that e.g.an object, such as e.g. a plunger, a stopper, a canula, a capillary or arod can be introduced into the chamber from outside. This opening willhereinafter be referred to as the outer opening. It is expresslyemphasised that the terms “inner opening” and “outer opening” purelyserve to differentiate between the terms, and no direct conclusions withregards to the position or the mutual orientation of the openings are tobe made. If necessary, the inner opening can also take over the functionof the outer opening.

In a preferred embodiment, the chamber is characterised in that at leastone of the openings (or, in variants with only one opening, thisopening) is connected to a movable plunger, sealing the opening tightly,which can be moved into or out of the chamber to open the chamber bymeans of an external canula or an external rod.

The inner opening of the chamber can be closed either by means of amovable stopper, a penetrable, easily-broken membrane or another movablesealing element. The outer opening optionally provided is sealed by aplunger, of such dimensions that it seals the chamber tightly on the onehand, but can be moved into the chamber by application of a force on theother hand.

In some embodiments, this plunger can have a hollow interior and have anopening. In these variants, the plunger can fill the entire chamberexactly and the active ingredient is then located inside it. Ifnecessary, the plunger is arranged so that it simultaneously seals theouter opening and the inner opening tightly, and no further sealingelements are required to store the active ingredient, tightly sealed,within the cavity of the plunger.

When the cartridge is inserted in the inhaler, a canula or rod locatedin the inhaler penetrates the closure-cap and thereby directly orindirectly opens the sealing element of the inner opening. This can e.g.be achieved by the canula tearing, penetrating, opening or moving asidethe sealing element, preferably starting from a point outside thechamber. If necessary, the canula can also open the sealing element froma point within the chamber. The sealing element may be a sealing foil,for example.

Alternatively, the canula may press the plunger into the chamber whenthe cartridge is inserted in the inhaler, so as to open the inneropening, e.g. the sealing element is either directly pierced, tom oropened by the plunger or is opened as a result of the over-pressureformed in the chamber. In doing this, the plunger is either pushed rightthrough the chamber by the canula until it falls through the inneropening into the container, or it remains in the chamber in such a waythat it does not interfere with the withdrawal of fluid through thecanula.

Instead of the plunger sealing off the outer opening, one or more otherequivalents can be used to perform the function of this element. Theseinclude stoppers, balls, spikes, platelets or seals of various types,e.g. sealing foils, clamp seals, plug seals or screw seals, or similar.

The apparatus according to the invention can be used as a cartridge forinhalers both for mono-preparations and also for combinationpreparations. In the case of mono-preparations, the active ingredient ispreferably stored in a stable formulation in the chamber, the furtheringredients of the pharmaceutical preparation to be applied, among themthe majority of the liquid component, in the container. In the case ofcombined preparations, the active components can be stored as a stableformulation either in one single chamber or in various chambers. If theactive ingredients which are used have significantly different shelflives, the more sensitive active ingredient can be stored in thechamber, as described above. The other, more stable active ingredientcan be stored together with the solvent or suspension agent located inthe container. Naturally, a prerequisite of this is that the latter isstable in the solvent over the intended storage time of several monthsor years.

The shelf life of the cartridge thus filled can be substantiallyextended, compared with a cartridge containing the finishedpharmaceutical preparation, by the delicate substances being stored in adifferent formulation from the one to be applied until the cartridge isinserted in the inhaler. An active substance can be stored in thechamber as a powder, granulate, in the form of a tablet, solution or asa suspension. Generally, for storage of the material or materials in thechamber, galenic formulations are preferred which promote simple andrapid dissolution of the active ingredient in the solvent when the twosubstances are brought together. Active substance concentrates arepreferred, which constitute a further aspect of the present invention.

The active substance concentrate according to the invention contains oneor more active substances which can be administered by inhalation andcan preferably be used for inhalative therapy. The invention thereforealso relates to the use of an active substance concentrate of this kindin inhalative therapy.

The active substance concentrate according to the invention may beconverted, by dilution with a pharmacologically acceptable liquidoptionally containing pharmaceutical excipients and additives, into apharmaceutical preparation (aerosol formulation) which is converted intoan inhalable aerosol with the aid of a nebuliser.

This diluent is preferably held in the container (2) when the cartridgeaccording to the invention is used. The pharmaceutical preparation whichis to be administered together with the active substance concentratedetermines the precise composition of the diluent.

The active substance concentrate according to the invention refers tosolutions or suspensions in which the active substance is dissolved orsuspended in highly concentrated form in a pharmaceutically suitableliquid and which are characterised in that the active substance can bestored therein for a period ranging from several months to possiblyseveral years without any deterioration in the pharmaceutical quality.

The term “active substance concentrate” denotes a solution or suspensionof one or more active substances which is or are present in highlyconcentrated form in a pharmaceutically acceptable liquid as a solutionor suspension. Suspensions are preferred, as they have provedparticularly stable on storage.

The term “highly concentrated” denotes a concentration of the activesubstance which is usually too high to allow the corresponding solutionor suspension to be used for inhalation for therapeutic purposes withoutbeing diluted. In the active substance concentrate, the concentration ofthe active substance (or substances) may exceed the concentration of thepharmaceutical preparation to be administered by a factor of 10 to 500,preferably 100 to 400, most preferably 250-350. According to theinvention, the active substance concentration in the active substanceconcentrate for suspensions is between 10 mg/ml and 1000 mg/ml,preferably between 75 mg/ml and 1000 mg/ml, more preferably between 75mg/ml and 500 mg/ml, most preferably between 100 mg/ml and 400 mg/ml,and most particularly between 250 mg/ml and 350 mg/ml. For solutions therange of concentrations is preferably between 10 mg/ml and 500 mg/ml,preferably between 75 mg/ml and 500 mg/ml, more preferably between 75mg/ml and 200 mg/ml and most preferably between 75 mg/ml and 150 mg/ml.Thus, for example, formoterol can be present in one embodiment of theformulation according to the invention in a concentration of between 10mg/ml and 500 mg/ml, preferably between 75 mg/ml and 500 mg/ml, morepreferably between 100 mg/ml and 400 mg/ml and most preferably between250 mg/ml and 350 mg/ml. For inhalation purposes, this formulation thenhas to be diluted to a concentration of about 0.9 to 1.5 mg/ml. Theconcentration data relate to mg of free base formoterol per ml of activesubstance concentrate.

The active substance(s) may be any substances which are suitable foradministration by inhalation and which are soluble or capable of beingsuspended in the abovementioned solvent or suspension agent. Thepreferred active substances are, in particular, betamimetics,anticholinergics, antiallergics, leukotriene antagonists and especiallysteroids and active ingredient combinations thereof.

Specific Examples Include:

-   Tiotropium bromide,    3-[(hydroxydi-2-thienylacetyl)oxy]-8,8-dimethyl-,8-azoniabicyclo[3.2.1]oct-6-ene-bromide

As betamimetics: Bambuterol Bitolterol Carbuterol Formoterol ClenbuterolFenoterol Hexoprenalin Procaterol Ibuterol Pirbuterol SalmeterolTulobuterol Reproterol Salbutamol Sulfoneterol Terbutalin

-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]    ethanol,-   erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butyl-amino)ethanol,-   1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.butylamino)ethanol.

As anitcholinergics: Ipratropium bromide Oxitropium bromide Tropiumchloride N-∃-fluoroethylnortropine benzylate methobromide Asantiallergics: Disodium cromoglycate Nedocromil Epinastin As steroids:Flunisolide Dexamethazone-21-isonicotinate Seratrodast Mycophenolatemofetile Pranlukast Zileutone Butixocort Budesonide DeflazacortBudesonide Fluticasone Promedrole Mometasone furoate TipredaneBeclometasone (or the 17, 21 dipropionate) Beclomethasone, DouglasIcomethasone enbutate Ciclometasone Cloprednole FluocortinebutylHalometasone Deflazacort Aclometasone Ciclometasone AlisactidePrednicarbate Hydrocortisone butyratepropionate Tixocortol pivalateAclometasone dipropionate Lotrisone Canesten-HC Deprodone Fluticasonepropionate Methylprednisolone aceponate Halopredone acetate MometasoneMometasone furoate Hydrocortisone aceponate Mometasone Ulobetasolpropionate Aminoglutethimide Triamcinolone Hydrocortisone MeprednisoneFluorometholone Dexamethazone Betamethasone Medrysone Flucloroloneacetonide Fluocinolone acetonide Paramethasone acetate Deprodonepropionate Aristocort diacetate Fluocinonide Mazipredone DifluprednateBetamethasone valerate Dexamethasone isonicotinate Beclomethasonedipropionate Fluocortolone capronate Formocortal Triamcinolonehexacetonide Cloprednol Formebolone Clobetasone Endrisone FlunisolideHalcinonide Fluazacort Clobetasol Hydrocortizone 17-butyrate DiflorasoneFluocortine Amcinonide Betamethasone dipropionate CortivazolBetamethasone adamantoate Fluodexane Trilostan Budesonide ClobetasoneDemetex Trimacinolone benetonide

-   9.alpha.-chloro-6-.alpha.-fluoro-11.beta.17.alpha.-dihydroxy-16.alpha.methyl-3-oxo-1,4-androstadiene-17.beta.-methylcarboxylate-17-propionate

Salbutamol, tiotropium and/or formoterol and the salts thereof,particularly formoterol, are preferably formulated in the concentrate assuspensions.

The term “pharmacologically suitable fluid” for the purposes of thepresent invention means a solvent or suspension agent which is not aliquefied propellant gas. Polar fluids are preferred, particularlyprotic fluids.

Examples of polar solvents or suspension agents for the active substanceconcentrate are e.g. dimethylsulphoxide or compounds which containhydroxyl groups or other polar groups, e.g. water oralcohols—particularly ethanol, isopropylalcohol, glycols, especiallypropyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether,glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid estersetc.

Examples of protic liquids, which are the most preferred solvents orsuspension agents in the context of the invention, are water, aqueoussaline solutions with one or more pharmacologically acceptable salt(s),ethanol or a mixture thereof. In the case of aqueous ethanol mixtures,the ratio by volume of ethanol to water or to the aqueous salinesolution is between 5:95 and 99:1, preferably between 40:60 and 96:4,most preferably between 75:25 and 96:4. A particularly preferred ratiois between 40:60 and 60:40.

For a saline solution as the solvent or suspension agent or as acomponent thereof, particularly suitable salts are those which displayno or only negligibly little pharmacological activity afteradministration. Saline solutions are preferably used for suspensionconcentrates. The addition of the salt significantly reduces thedissolving power of water for the active substance or substances, so asto achieve a stabilising effect on the suspended particles. If desired,saturated saline solutions may be used. The quantity of salt depends onthe precise composition of the solvent or suspension agent and itsability to dissolve the active substance. For example, formoterol shouldbe present in dissolved form in an amount of less than 0.5% by weight,preferably less than 0.1% by weight, in an aqueous formoterol suspensionin the sense of the active substance concentrate according to theinvention, these amounts being based on the total amount (weight) offormoterol. However, if the amount of dissolved material is above thespecified levels, it can be reduced to below these levels by theaddition of salt.

As a rule, the solubility can be halved by the addition of salt, and insome cases reduced to one fifth or even less. Preferred are salinesolutions with a salt content of up to 50% by weight, especially up to20% by weight.

Both inorganic and organic salts may be used as the salts. Inorganicsalts such as sodium chloride, alkali metal or ammonium halogen saltsare preferred. Sodium chloride is particularly preferred. Suitableorganic salts are, for example, the sodium, potassium or ammonium saltsof the following acids: ascorbic acid, citric acid, malic acid, tartaricacid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acidand/or propionic acid.

Cosolvents may be added to the solvent or suspension agent. Co-solventsare suitable for increasing the solubility of additives and optionallythe active substance (or substances).

Preferred cosolvents are those which contain hydroxyl groups or otherpolar groups, for example alcohols—especially isopropyl alcohol,glycols—especially propylene glycol, polyethylene glycol, polypropyleneglycol, glycol ether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters, provided that these are not alreadyused as the solvent or suspension agent.

Other excipients and additives may also be added to the active substanceconcentrate according to the invention.

The term excipients and additives in this context denotes anypharmacologically suitable and therapeutically useful substance which isnot an active substance but can be formulated together with the activesubstance (or substances) in the pharmacologically suitable solvent orsuspension agent in order to improve the qualitative properties of theactive substance concentrate or the pharmaceutical preparation which isto be obtained by dilution ready for inhalation. Preferably, thesesubstances have no pharmacological activity or, in the context of thedesired therapy, no appreciable or at least no undesirablepharmacological activity. The excipients and additives include, forexample, surfactants for stabilising suspensions, other stabilisers,complexing agents, antioxidants and/or preservatives which prolong theduration of use of the finished pharmaceutical formulation, flavourings,vitamins, and/or other additives known in the prior art.

As surfactants the active substance concentrate may contain, forexample, soya lecithin, oleic acid, sorbitan esters such as sorbitantrioleate or other surfactants known from the prior art in the usualconcentrations.

It has been found that addition of an organic or inorganic acid,preferably in combination with a complexing agent, leads to improvementin the stability (shelf life) of some medicaments which contain ethanolas a solvent, especially medicaments containing steroids. This appliesespecially to medicament preparations which contain formoterol,flunisolide or its hydrate or hemihydrate or budenoside as activeingredient.

Examples of inorganic acids which are preferred in this respect are:hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid.Examples of especially suitable organic acids are: ascorbic acid, citricacid, malic acid, tartaric acid, maleic acid, succinic acid, fumaricacid, acetic acid, formic acid, propionic acid and others. The preferredacids are hydrochloric acid and/or fumaric acid.

The concentration of acid is selected so that the active substanceconcentrate has a pH of between 2.0 and 7.0, preferably between 4.0 and6.0 and most preferably between 4.5 and 5.5.

Examples of complexing agents which may be used on their own or inconjunction with an acid include EDTA (ethylenediaminetetraacetic acid,or a salt thereof, such as the disodium salt), citric acid,nitrilotriacetic acid and the salts thereof. The preferred complexingagent is EDTA.

Preservatives can be used to protect the concentrate from contaminationwith pathogenic germs. Those preservatives which are known in the priorart are suitable, especially benzalkonium chloride or benzoic acid, orbenzoates such as sodium benzoate.

Suitable antioxidants are the well known pharmacologically acceptableantioxidants, especially vitamins or provitamins, as present in thehuman body, i.e. ascorbic acid or vitamin E.

If the active substance or substances is or are present in the activesubstance concentrate according to the invention as a suspension, theparticles are preferably formulated in a particle size of up to 20 :m,preferably up to 10 :m and especially preferably up to 5 :m.

Preferred active substance concentrates contain only one or two activesubstances; active substance concentrates having one active substanceare particularly preferred.

Suspensions are most preferred as the active substance concentrate.

The active substance concentrate according to the invention has theadvantage that an active substance can be formulated in such a way as toremain stable over a fairly long period of time. It is not necessary forthe concentrate to correspond to the composition of the finishedpharmaceutical preparation, apart from the concentration of the activesubstance. For example, the pH of the concentrate may differsubstantially from the pH of the pharmaceutical preparation which is tobe administered, if this ensures a more stable solution or suspension ofan active substance.

The active substance concentrate according to the invention is notusually suitable as such for direct medicinal use, particularly forinhalation. As already explained, use of the active substanceconcentrate comprises converting it into a pharmaceutical preparation(aerosol formulation). The term “pharmaceutical preparation” denotes aformulation of a pharmaceutical substance suitable for inhalationwherein a pharmaceutical substance or mixture of substances can beadministered in the required and/or recommended concentration.

The pharmaceutical preparation is preferably such that it can beadministered by inhalation using a suitable nebuliser.

A preferred method of converting the active substance concentrate into apharmaceutical preparation suitable for administration is by dilutingthe active substance concentrate according to the invention with apharmacologically suitable solvent or suspension agent.

In order to obtain the pharmaceutical preparation for administration,the active substance concentrate is diluted until the pharmaceuticalpreparation ready for inhalation is produced. The pharmaceuticalpreparation to be administered determines, together with the activesubstance concentrate in the chamber (17), the precise composition ofthe diluent in the container (2).

Examples of formulations which are suitable for administration aredisclosed in WO 97/01329, to the contents of which reference isexpressly made. If such formulations are to be administered within thecontext of the present invention, the active substance concentrate inthe chamber (17) and the diluent in the container (2) should be suchthat when they are mixed together they produce a formulation accordingto or analogous to that of WO 97/01329.

In a formulation of this kind suitable for administration, theproportion of dissolved medicament in the finished pharmaceuticalpreparation is generally between 0.001 and 5%, preferably between 0.05and 3%, particularly between 0.01 and 2%, these figures referring topercent by weight. In the case of solutions as the finishedpharmaceutical preparation the maximum concentration of the medicamentis dependent on the solubility in the solvent and the dosage required toachieve the desired therapeutic effect.

As already mentioned, aqueous or aqueous saline solutions, preferablyaqueous solutions, which may contain ethanol, are preferred inter aliaas solvents or suspension agents for the finished pharmaceuticalpreparation, i.e. the preparation suitable for inhalative or nasalapplication. Solutions with at least 30% (v/v) ethanol are preferred,and especially preferably with at least 50% (v/v). Especially preferredare solutions with an ethanol content of over 95% (v/v). Concentrationis given in percent by volume (v/v), the remainder being water oraqueous saline solution. Ethanol which already contains small quantitiesof water is especially preferred—for example 96% ethanol, 4% water(v/v)—so that it is no longer hygroscopic and evaporates azeotropically.

The pharmaceutical preparation to be applied together with the activesubstance concentrate in the chamber (17) determine the exactcomposition of the diluent in the container (2).

The medicament formulation ready for use is only prepared when thecartridge is inserted in the inhaler for it is only by this action thatthe contents of the chamber (17) are mixed with those of the container(2). It should be pointed out here that the individual components oringredients of the diluent are defined as specified in connection withthe active substance concentrate, where these components or ingredientshave been described or unless otherwise specified.

Preferred solvents or suspension agents for the dilution arepropellant-free liquids, preferably polar, more particularly proticliquids.

Particularly preferred diluents are water, aqueous saline solutions withone or more pharmacologically acceptable salts, ethanol or a mixturethereof, mixtures of water and ethanol being particularly preferred. Inthe case of aqueous ethanol mixtures, the ratio by volume of ethanol towater or to the aqueous saline solution is such that the inhalablepharmaceutical preparation has a formulation with at least 30% (v/v)ethanol, most preferably with at least 50% (v/v). Especially preferredare pharmaceutical preparations with an ethanol content of over 95%(v/v). Concentration is given in percent by volume (v/v), the remainderbeing water or aqueous saline solution. Ethanol which already containssmall quantities of water is especially preferred—for example 96%ethanol—so that it is no longer hygroscopic evaporates azeotropically.

It is neither obvious nor necessary for the diluent to be identical tothe solvent or suspension agent of the active substance concentrate. Ifdesired, the latter may also contain only one or a few constituents ofthe diluent.

It should be expressly pointed out here that the cosolvents and/orexcipients or additives and/or active substances mentioned above inconnection with the active substance concentrate according to theinvention may also or only be dissolved or suspended in the diluent.

Preferred embodiments of the diluent contain preservatives and/orcomplexing agents.

Optionally, the diluent may contain a buffer substance, e.g. trisodiumphosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate,Na-EDTA, EDTA, mixtures thereof and other substances known from theprior art. Preferred substances are sodium dihydrogen phosphate,disodium hydrogen phosphate, trisodium hydrogen phosphate, potassiumdihydrogen phosphate, potassium hydrogen phosphate, tripotassiumhydrogen phosphate, and mixtures thereof. Buffer substances areparticularly beneficial when the active substance concentrate suitablefor storage according to the invention has a pH which differssignificantly from that which is desired for the application, e.g. whenthis increases the stability of the active substance during storage. Inthis case the buffer substance is present in the diluent in aconcentration such that, after mixing the active substance concentratewith the diluent, an aerosol formulation suitable for administration isobtained with the desired pH, preferably between 2.0 and 7.0,particularly between 4.0 and 6.0. most preferably between 4.5 and 5.5.

In a preferred embodiment, the pharmaceutical preparation contains acomplexing agent which is preferably selected from a complexing agentmentioned in connection with the active substance concentrate. Thequantity of complexing agent is up to 100 mg/100 ml, preferably up to 50mg/100 ml. The preferred complexing agent is EDTA.

A preferred pharmaceutical preparation contains, for example, in thepharmaceutical preparation which is to be administered, 1.667% by weightof flunisolide, 0.01 mg/100 ml EDTA and ethanol (96% v/v) as solvent. Itis adjusted to a pH of between 3.0 and 4.0, preferably 4.0, by theaddition of acid (hydrochloric acid).

If the diluent contains one or more active substances, the diluent maycontain an organic or inorganic acid, preferably combined with acomplexing agent, as a stabiliser, particularly in the case ofsteroid-containing drugs. This applies particularly to pharmaceuticalpreparations which contain formoterol, flunisolide or the hydrate orhemihydrate thereof or budesonide as active substance.

As already mentioned, the pharmaceutical preparation which is to beadministered together with the active substance concentrate determinesthe precise composition of the diluent.

Preferred pharmaceutical preparations contain one or two activesubstances; pharmaceutical preparations having one active substance areparticularly preferred.

Neither the active substance concentrate suitable for storage accordingto the invention nor the pharmaceutical preparation for administrationobtained by dilution contains a propellant.

Preferably, the mixing takes place at ambient temperature and undernormal pressure. One advantage of the active substance concentrateaccording to the invention is that it can be converted by dilution intoa therapeutically effective formulation and/or one which is suitable foruse in a nebuliser within a very short time, e.g. within a few minutesor possibly a few seconds. The mixing can also be done by patients, whogenerally have no pharmaceutical knowledge.

Alternatively to the separation of the individual components of thepharmaceutical preparation to be administered, as described earlier, forthe purpose of inhalation, the active substance may also be stored inthe container (2), preferably as a storable solution or suspension,which does not necessarily constitute the pharmaceutical preparation tobe administered. In this case, the concentration of the activesubstances corresponds to the concentration of the pharmaceuticalpreparation to be administered as described above (plus or minus 10% byweight). The chamber (17) then contains the other excipients andadditives, preferably those mentioned above, for producing thepharmaceutical preparation which is to be administered. These may thentake the form of powders, tablets, suspensions or solutions.

For example, an active substance may be stored as a solution orsuspension in the container (2) at a pH which is more acidic or morebasic than that of the pharmaceutical preparation to be administered. Inthis case, the chamber (17) may contain buffers, for example, preferablythose described above. When the cartridge is inserted in the inhaler,the pH desired for administration is achieved by mixing the contents ofthe chamber (17) with the formulation in the container (2). For example,a liquid formulation containing tiotropium bromide as active substancemay be stored in the container (2) at a pH of less than or equal to 3.0.The chamber (17) then contains buffer substances such as those mentionedabove, e.g. the sodium and potassium di- and mono-hydrogen phosphates,in an amount which ensures that a pH of from 3.0 to 7.0, preferably from3.0 to 4.0, is obtained when these buffers are mixed with the tiotropiumformulation. These figures are merely an example of the formulationpossibilities for tiotropium bromide and are not necessarily identicalfor other active substances mentioned. The active substance can also bestored in the container (2) as a suspension while the chamber (17)contains a pharmacologically acceptable solvent, so that a solutionformulation is produced when they are mixed together.

The preferred volume of the formulations in the chamber (17) andcontainer (2) is crucially determined by the volumes of the chamber (17)and container (2). For storage in the abovementioned cartridge, inpreferred embodiments, the quantity of active substance concentratesuitable for storage according to the invention is selected tocorrespond to a volume of 0.001 to about 0.05 ml, preferably 0.001 to0.02 ml.

The abovementioned examples demonstrate that the two-chamber cartridgecan be used to store different components of an active substanceformulation separately until the cartridge is inserted in theappropriate inhaler. It is not necessary for the components thus storedto be capable of being administered per se. All that is required is thatthe components thus stored are mixed together when the cartridge isinserted in the appropriate inhaler so as to produce the desiredformulation ready for administration.

DESCRIPTION OF THE CARTRIDGE ACCORDING TO THE INVENTION IN DETAIL

The invention will hereinafter be described in greater detail with theassistance of concrete embodiment examples.

FIG. 1 shows an axial section along the longitudinal axis of thecartridge (1), according to the invention, comprising a container (2)for the solvent and a closure-cap (3) wherein substantially only thesealing features are listed. The further characteristics of theclosure-cap (3) are described in more detail in the following FIGS. 3 to11.

FIG. 2 shows an embodiment of the closure-cap (3) with an alternativesealing concept wherein, analogous to FIG. 1, only the sealing featuresare listed in detail. The container (2) is only indicated.

FIG. 3 shows an embodiment of the closure-cap (3) with chamber (17), aplunger (21) and a guide tube (16) in axial section.

FIGS. 4 a to 4 g show various embodiments of the plunger (21) in axialsection.

FIG. 5 shows an embodiment of the closure-cap (3) with a hollow plunger(21) for receiving the active ingredient, in axial section.

FIG. 6 shows a further embodiment of the closure-cap (3) with a hollowplunger (21), in axial section.

FIG. 7 shows a further embodiment of the closure-cap (3) with a hollowplunger (21), in axial section.

FIG. 8 shows a further embodiment of the closure-cap (3) with a hollowplunger (21), in axial section.

FIG. 9 shows an embodiment of the closure-cap (3) with a plunger (21), aguide tube (16) and a chamber (17) in which two compartments are formed,in axial section.

FIG. 10 shows an embodiment of the closure-cap (3) without a preciselyfitting guide track for the canula (15), in axial section.

FIG. 11 shows an embodiment of the closure-cap (3) where the chamber(17) has only one opening which is sealed with a plunger (21).

FIG. 12 shows an embodiment with a chamber (17) that can be torn off atthe connecting piece (7).

FIG. 1 shows an axial section along the longitudinal axis of thecartridge (1) according to the invention, comprising a container (2) forthe solvent and a closure-cap (3). The drawing shows only thosecharacteristics of the closure-cap (3) which are necessary for sealingthe container (2). Further characteristics of the closure-cap (3) willbe covered in greater detail in the subsequent figures.

The container (2) according to the invention comprises a “jacket” (4)and an easily-deformable inner bag (5). The inner bag (5) lines theinner wall of the jacket (4), but is not fixed to the jacket (4) exceptfor an area in the neck of the container (2) and the web (6). Theadvantage of a deformable inner bag which is attached in this manner isthat a fluid can be extracted therefrom via a canula without causing anunder-pressure in its interior which would work against furtherextraction, or without the inner bag disadvantageously collapsing duringremoval of the fluid. In the following text, especially in the followingclaims, no further distinction is drawn between “container (2)”, jacket(4) and “inner bag (5)”, rather the term “container (2)” is exclusivelyused.

The closure-cap (3) has a device—here in the form of an immersedconnecting piece (7)—through which some of the contents are displacedfrom the container (2) during the sealing process. Preferably theconnecting piece (7) is such that, when the cap (3) is firmly sealingthe neck of the container (2), the connecting piece (7) does not touchthe neck of the container (2), or touches it only so that a gap isformed between the connecting piece (7) and the inner surface of thecontainer (2) in the closed position of the cartridge, to allow gas orfluid to escape from inside the container (2) along the connecting piece(7) during the closing process. Alternatively, the connecting piece (7)may have one or more vertical notch(es) on its surface, along its wholelength, through which gas or fluid can escape from within the container(2) during the closing process (not shown). In this case the outerdiameter of the connecting piece (7) may correspond to the innerdiameter of the neck of the container. In the closed position, the cap(3) seals the container (2) tightly so that no more gas or liquid canescape from inside the container (2).

A circumferential bulge (8), disposed in the interior on the lower edgeof the head of the closure-cap (3), engages in the sealing positionunder a circumferential cylindrical ring (9) located on the outside ofthe container neck. In the sealed position, the intermediate spacebetween the flat part of the closure-cap (3) and the upper edge of thecontainer neck, which is optionally provided with a circumferential rib(10) for better sealing, is filled by a sealing ring (11) and in thisway the interior of the container (2) is sealed. The interior diameterof the sealing ring (11) is chosen expediently so that it lies tightlyagainst the connecting piece (7). The medium (gas, air or fluid) forcedfrom the interior of the container (2) as a result of the closingprocess can escape via one or more ventilation openings (12) on the headof the closure-cap (3). The ventilation opening or openings (12) canalso be located in other places on the cartridge, for example laterallyin the cylindrical part of the cap.

FIG. 2 shows an embodiment in axial cross section where the closure-cap(3) is sealed by an aluminium sleeve (13) which is crimped. Again, onlythose characteristics of the closure-cap (3) which are necessary forsealing the container (2) are represented in the diagram. All othercharacteristics of the closure-cap (3) are described in greater detailin the following figures. The container (2) is only shown in part.

The sleeve (13) is shaped so that it has a central opening (14) for thecanula (15) to pass through. The continuation of the opening (14) as aguide tube (16) for the canula (15) through the closure-cap (3) is onlyshown in part.

The opening (14) can be sealed by a septum as a seal of origin or inorder to protect it from dust and other impurities. This method ofsealing is, for example, known from injection ampoules. A seal of originof this kind can also be formed in a closure-cap according to FIG. 1.

In the following FIGS. 3 to 11, various embodiments of the closure-cap(3) are shown in axial section. The chamber (17) is represented as anintegral component of the connecting piece (7). The container (2) is notillustrated. All figures show the closure-cap with a sealing system asrepresented in FIG. 1. Analogous embodiments can also have a sealingsystem according to FIG. 2, but these are not shown.

FIG. 3 shows an embodiment of a closure-cap (3) in axial section. Thecentral element of the closure-cap (3) is a chamber (17) whichterminates at the foot of the connecting piece (7) and which containsthe active ingredient(s) (22) described, which may be, for example, oneor more active substances, excipients and additives which may be in theform of a concentrated solution or suspension, a powder, granules, orone of the other forms described above. Preferably, the chamber containsthe active substance concentrate described above. The chamber (17) hastwo openings, (18) and (19). An object can be introduced into thechamber (17) from outside via the opening (18), the contents of thechamber (17) can be emptied into the container (2) via the opening (19).The opening (19) is sealed with a separating element (20) which projectsbeyond this and is firmly attached to the connecting piece (7). Theopening (18) is sealed by a plunger (21). From the top end of theclosure-cap (3), a guide tube (16) for a capillary or canula (15) forthe extraction of fluid leads to the plunger (21). A septum or an O-ringseal (23) can be provided in the guide tube.

The position of the separating element (20) or the plunger (21) can varyover a wide range within the interior of the connecting piece (7), butit is preferably arranged as a function of the quantity of activeingredient (22) so that the interior space formed by the separatingelement (20) or by the separating element (20) and the plunger (21)contains the smallest possible volume of gas (air), preferably no gas atall.

The separating element (20) can, for example, be a foil which can betorn by pressure or which can easily be torn open by a sharp or pointedobject. Heat-sealed sealing foils which are impervious to diffusion arepreferred. These kind of sealing foils may contain an aluminium layer,for example. In one embodiment, the separating element (20) can havefrangible points where it is attached to the side wall of the connectingpiece (7) so that it tears open at these frangible points when apressure or a force is exerted upon it. As an alternative to a sealingfoil, the opening (19) can also be sealed by a stopper or a plunger (notillustrated).

The plunger (21) is made from a material which is so hard that a roundedcanula cannot penetrate it, or is so inelastic that the plunger does notremain attached to the canula when the canula is pressed firmly againstit. A preferred material is an elastomer, soft plastic and/or plasticsuch as polyethylene, silicone, EPDM(ethylene-propylene-diene-copolymer).

The shape of the plunger (21) may be cylindrical, for example. In anycase, it is shaped so that it tightly seals the opening for which it isprovided. The plunger (21) preferably has a length which is greater thanits diameter, e.g. by a factor of between 1.2 to 2, preferably by afactor of 1.5. In this way, the plunger (21), when it is moved, isguided along its outer surface and canting is prevented. FIGS. 4 a to 4g show further embodiments of the plunger (21) where one or more spikesor cutting edges (FIGS. 4 a and 4 b) are provided where one side issloped (FIG. 4 c) or where the plunger (21) tapers to a point (FIG. 4d). The spikes or cutting edges provided can have a very small diameter(μm to mm) and are at most long enough to reach, or almost reach, theseparating element (20) in the starting position of the plunger (21),i.e. before the plunger (21) is moved through the canula (15).

A further preferred embodiment of the plunger (21) is shown in FIG. 4 e.The plunger has a recess (28) in the form of a hollow space which isopen on one side. The opening in the recess (28) faces towards the headof the closure-cap (3), i.e. in the direction of the capillary or canula(15). The interior diameter of the opening or the recess (28) is greaterthan the exterior diameter of the canula (15). In cross section, theplunger (21) has the shape of a U with optionally angled edges. The baseof the recess (28) forms the point on the plunger (21) where the canula(15) can act in order to press the plunger (21) into or through thechamber (17). The advantage of this design and arrangement is that theplunger (21) can easily taper as a result of the pressure of the canula(15) on the base of the recess (28) at the opposite end, that is, on theside of the plunger (21) which directly closes the opening (18). Thatis, by the application of pressure on the canula (15), the shape of theplunger (21), in cross section, changes from a U-shape to almost aV-shape. This makes it easier for the plunger (21) to pass through theopening (18). A further advantage of this shape alteration of theplunger (21) caused by pressure from the canula (15) is that thepressure of the plunger (21) on the walls which hold it is reduced sothat even a tightly-fitting plunger (21) is released and can be moved bythe canula (15) without canting. This embodiment is especiallyadvantageous when the plunger (21), as e.g. shown in FIG. 3, seals thechamber (17) from within against the opening (18).

In FIG. 4 f a plunger (21) with a hollow space (24) is represented whichexactly, or almost exactly, fills the entire chamber (17) along itslength and width. In this connection, “exactly” means that the plunger(21) has the same external dimensions as the interior of the chamber(17) or is possibly up to 5% wider than the chamber (17). The term“almost exactly” means that the plunger (21) is marginally smaller inits diameter and/or in its length than the interior of the chamber (17).It is preferred that the plunger (21) is designed as an exactly-fittingplunger. Such a variant can be advantageous on filling the closure-cap(3) but also when moving the plunger through the chamber (17) by meansof the canula (15). The plunger (21) can hereby be so bedded into thechamber that the opening of the hollow space (24) is sealed by theseparating element (20) (FIG. 5), or that the opening of the hollowspace (24) is tightly sealed by the side wall of the chamber (17) (FIG.6). The variant 4 g shows another embodiment of a plunger (21) of thetype represented in FIG. 4 f in axial section, wherein the hollow space(24) is separated into two chambers by a partition for separatelyaccommodating different ingredients in the chamber (17). Here, too, theseparating element (20) seals the plunger on its open side. The openingof the plunger (21) according to FIGS. 4 f and 4 g can extend eitherover the entire width (illustrated) or only a part thereof (notillustrated).

In order to prevent canting of the plunger (21), guide means can beprovided on the plunger and/or the side walls of the chamber (17), e.g.guide rails or guide ribs (not illustrated). In order to improve thesliding of the plunger (21) through the opening (18) and the chamber(17), the plunger (21) or the wall of the chamber (17) can be coatedwith a pharmacologically-acceptable lubricant. Such lubricants are knownin the prior art and include e.g. sorbitan esters, e.g. sorbitantrioleate, oleic acid, lecithin and other fatty acids, fatty alcohols,esters of fatty acids and similar.

The guide tube (16) for canulae or capillaries can be designed so as toseal an exactly-fitting capillary (15) tightly to the connecting piece(7) when it is pushed into the connecting piece (7). If necessary, theguide tube (16) tapers as its distance from the head of the closure-cap(3) increases. Alternatively or in addition, a penetrable septum or anelastic O-ring seal (23) can be disposed at any desired position in theguide tube (16). For the sake of simplicity, the expression “septum(23)” will hereinafter be used for both a penetrable septum and anelastic O-ring seal (23). As the name implies, it is the task of theguide tube (16) to guide the canula or capillary (15) along a predefinedpath through the closure-cap (3) without any complications.

At the side which is open towards the head end, the guide tube (16) canhave a seal of origin or a protection from impurities. These functionsmay also optionally be performed by the septum (23).

In a preferred embodiment, the chamber (17) has a constant interiordiameter along its entire longitudinal axis. The openings (18) and (19)are located perpendicular to the longitudinal axis on the upper side orthe lower side of the chamber (17). Both openings extend over the entirediameter of the chamber (17). The plunger (21) can have a marginallygreater exterior diameter than the interior diameter of the chamber(17), especially when it is in its sealing position within the chamber(17) (FIG. 3). In this way, better sealing of the opening (18) isachieved. In addition, this has the advantage that the plunger (21)completely empties the chamber (17) when the former is pushed throughthe latter.

As already described, embodiments with a hollow plunger (21) arerepresented in FIGS. 5 and 6, where the active ingredient or ingredients(22) is or are stored in the hollow area (24) of the plunger instead ofdirectly in the chamber (17). In such embodiments, the canula (15)pushes the plunger (21) right through the chamber (17) until the plungerfalls into the container (2) and the contents (22) of the plunger (21)are dissolved or suspended by means of the solvent in the container (2).

Such a variant can also be designed so that the plunger cannot be pushedright through the chamber (17), but only far enough for the activeingredient (22) to be poured into the container (2) (not illustrated).In this case, guide rails and/or detents are located on the outer wallof the plunger (21) and/or the inner wall of the chamber (17), whichprevent the plunger being pushed entirely through the chamber (17) (notillustrated). In this case, the side wall of the chamber (17) can alsohave an opening which remains sealed by the plunger (21) until theplunger (21) is moved by the canula (15). Here, the opening is designedso that the aerosol formulation ready for use can be removed through itby means of the canula (15). The plunger (21), the chamber (17), thecanula (15) and the guide rails and/or detents are hereby designed sothat the plunger (21) cannot block the canula (15) after it has beenpushed by the canula into its end position. If desired, the canula(15)may only bring about the initial movement of the plunger (21) throughthe chamber (17), after which the plunger (21) falls into the detent ofits end position, e.g. as a result of gravity or as a result of afurther mechanism. This prevents the plunger (21) from blocking thecanula (15).

FIG. 7 shows a further variant with a hollow plunger (21) which entirelyfills the chamber (17). The plunger (21), with its opening, is pluggedonto a stopper-like projection (27), provided in the connecting piece(7), which simultaneously holds the plunger (21) in the chamber (17) andtightly seals the opening of the plunger (21). In this variant, theopening of the plunger (21) is designed so that only a part of the sidewall is open. The guide tube (16) leads to a closed part of the sidewall of the plunger (21) so that the canula (15) can act at this pointin order to release the plunger (21) from its anchoring with theprojection (27) and push it into the container (2). The plunger (21) canalso have several openings which are sealed by a plurality ofstopper-like projections (27) in the connecting piece (7) (FIG. 8).

In such variants, the inner opening (19) does not necessarily need to besealed by a separating element (20), although this might be the case(not illustrated).

FIG. 9 shows an embodiment of the closure-cap (3) similar to that inFIG. 3, where the chamber (17) is divided into two compartments by meansof a separating element (25). The separating element (25) is easy toopen or remove, in a similar manner to the separating element (20). Thecompartments serve to accommodate two or more active ingredients oradditives separately. In an analogous manner, more than two compartmentscan be provided (not illustrated).

In one embodiment, where the chamber (17) has at least two compartments,a pharmacologically-acceptable solvent with a very good dissolving powerfor the active ingredient can be stored in one of the compartments, e.g.the compartment which is not sealed by the separating element (20)(upper compartment). Such a solvent may be of the type definedhereinbefore, for example, or another solvent known from the prior art,e.g. pure ethanol.

In such an embodiment, the plunger (21) can be provided with one or morespikes or cutting edges. In a two-stage mechanism, the plunger (21) isfirstly only pushed far enough into the chamber so that the separatingelement (25) is opened and the solvent flows from the upper compartmentinto the lower compartment and dissolves or suspends the activeingredient (22) which is located there. In a second step, the plunger(21) can then be moved further so that the separating element (20) isopened and the dissolved or suspended active ingredient flows into thecontainer (2).

In this case, too, a penetrable membrane can be provided in place of theplunger (21). In this case, the dimension of the guide tube (16) and theupper compartment is designed so that the canula (15) can just penetrateor tear open the separating element (25), so that the solvent flows intothe lower compartment and dissolves or suspends the active ingredient.The separating element (20) is then such that, or is connected with theconnecting piece in such a way that the solvent destroys the connectionof the separating element (20) with the connecting piece (7) to enablethe solution or suspension of active ingredient to flow unimpeded intothe container (2). The last-described variants are advantageous when theactive ingredient in the chamber (17) is a solid which is not dissolvedor suspended sufficiently rapidly in the solvent provided for thepharmaceutical formulation.

Alternatively, mixing of the solvent in the upper compartment with thecontents (22) in the lower compartment can also take place directlybefore installation of the cartridge into the inhaler, e.g. by the userpressing the closure-cap (3) against the container (2), thisimplementing the first stage of the mechanism by means of a suitableapparatus. A mechanism of this type can be provided irrespective of thenumber of compartments in the chamber (17), i.e. if necessary only asingle compartment can be provided in the chamber (17).

FIG. 10 shows an embodiment analogous to that of FIG. 3, where insteadof the exactly-fitting guide tube (16) for the capillary (15), a widerguide tube (26) is provided in the closure-cap (3). In this embodiment,the plunger (21) is held on the side orientated towards the head of theclosure-cap (3) by a penetrable septum or an elastic O-ring seal (23).In this case, too, the guide tube (26) can be sealed at its open end atthe head of the closure-cap by a seal of origin or a protection fromimpurities.

In other embodiments, no guide tube (16) or no tube (26) is provided. Inthese cases, a septum or an elastic O-ring seal (23) is integrated intothe upper side of the closure-cap (3), under which the plunger (21) orthe chamber (17) is directly located. Such an embodiment is notillustrated, but is very similar to the embodiment shown in FIG. 10.

In the embodiments in FIGS. 3 to 10 described hitherto, the chamber(17), the opening (18), the opening (19) and the plunger (21) aredimensioned so that the plunger (21) tightly seals the opening (18), butcan be completely pushed through the chamber (17) and the opening (19)by means of pressure on the capillary (15). In the case of theembodiments of FIGS. 3 to 6 and 9 and 10, the separating element (20)opens via the movement of the plunger (21) into the chamber (17) as aresult of the force exerted through the capillary or the canula (15), inthat it e.g. tears as a result of the pressure increase in the interiorof the chamber (17) and/or is penetrated by one or more spikes orcutting edges provided on the plunger (21). The contents of the chamber(17) flow into the container (2) with the solvent as a result of theopening of the separating element (20). The shape and arrangement of theelements involved in this process are such that the canula (15) does notcome into contact with the contents of the chamber either before orafter being mixed with the contents of the container (2). In this way,blockage of the canula (15) is prevented.

Another embodiment is represented in FIG. 11 and relates to aclosure-cap (3) where the interior of the connecting piece (7) issubstantially hollow and thus forms the chamber (17). The guide tube(16) leads from the head of the closure-cap (3) through the chamber (17)up to the plunger (21) which is held by the lower side wall of thechamber (17) and tightly seals the chamber (17) and the guide tube (16).The plunger (21) simultaneously seals the guide tube (16) opposite thechamber (17). A septum (23) is located in the guide tube. The plunger(21) is designed so that it can be pushed into the container (2) bymeans of the canula or capillary (15). If necessary, the chamber (17)can be divided into various compartments by means of partitions (notrepresented) which are provided parallel to the longitudinal axis of theconnecting piece, all of these partitions being sealed by the plunger(21) (not illustrated).

FIG. 12 shows a closure-cap with a connecting piece (7) in which a guidetube (16) with a penetrable septum (23) is provided. The guide tube (16)reaches up to the foot of the connecting piece (7) where the chamber(17) is suspended via deliberately produced frangible points (29). Inthis embodiment, the opening (19) is parallel to the longitudinal axisof the connecting piece (7) and is tightly sealed with the separatingelement (20). The separating element (20) extends over the opening (19)and is fixedly connected to the connecting piece (7) at this point (30).When a capillary (15) penetrates the septum (23) and presses on thechamber (17), firstly the frangible points (29) break. The separatingelement (20) over the opening (19) is then torn open as a result of theinherent weight of the chamber (17) or the further pressure via thecanula (15) so that the separating element (20) remains connected withthe connecting piece (7); however the chamber (17) itself falls into thecontainer (2). If necessary, the frangible points (29) can be designedas an easily-tom foil or adhesive strip, which connects the chamber (17)with the connecting piece (7) at the side opposite the separatingelement (20).

Alternatively, the chamber (17) can be exclusively connected with theconnecting piece (7) via the separating element (20). In this case, thefrangible points (29) are not provided.

If an active ingredient is to administered as a solution and is to bestored in the chamber (17) as a suspension, embodiments according toFIGS. 3, 4, 9 and 10 are preferred, especially those where theseparating element (20) is designed in the form of a sealing foil withan aluminium coating. These embodiments have the advantage that anover-pressure is formed by pressure of the plunger (21) in the chamber(17), which causes the separating element (20) to tear and thesuspension to flow under pressure from the chamber (17) and dissolverapidly in the solvent in the container (2).

The container and the closure-cap are generally produced from adeformable plastic. The walls of the container are produced so that theywill sufficiently give or collapse on removal of the fluid. Theseparating element (20) generally consists of a thin plastic foil. Theseparating element (20) preferably contains a thin aluminum foil.

The cartridge with medicament formulations for an inhaler, according tothe invention, should have a long shelf-life. For this purpose, it isessential that the solvent cannot diffuse from the container (2) intothe chamber (17) which contains the active ingredient before use. Apartfrom having a chamber with sufficiently thick walls, an additionalaluminium coating can be applied to the outer or inner surfaces of thechamber (17).

The cartridge is preferably of such a size that it can be inserted ininhalers, such as e.g. those disclosed hereinbefore. The preferredcapacity of the container (2) is approximately 5 ml, that of the chamber(17) from 0.001 to 0.5 ml, preferably from 0.001 ml to 0.2 ml, morepreferably 0.001 ml to 0.05 ml, most preferably from 0.001 ml to 0.03ml.

Suitable plastics—for example polystyrene (PS), polycarbonate (PC),polymethyl methacrylate (PMMA), acrylonitrile/butadiene/styrenecopolymers (ABS), polyethylene terephthalate (PET) and other plasticsare available to the skilled person for the production of suchcontainers, and also for production of the closure-cap.

It should be emphasised that the use of the cartridge with the chamber(17) in the inhaler requires essentially the same manipulation by thepatient as the use of a conventional cartridge.

EXAMPLES OF THE ACTIVE SUBSTANCE CONCENTRATE ACCORDING TO THE INVENTION

In the following text, by way of example, individual formulations arelisted with concentration or quantity data. However, the examplesrepresent only a selection from the aforementioned possible formulationcombinations.

Example 1

5 mg of formoterol (particle size:5 μm) are metered as a suspension with0.015 ml of water into the chamber (17). The pH is adjusted to 5.0 usingfumaric acid. The concentration of the formoterol is 333 mg/ml.

4.5 ml of a 1:1 water/ethanol (v/v) solution are placed in the container(2). The solution contains 0.45 mg benzalkonium chloride and 2.25 mgNa-EDTA and is adjusted to a pH value of 5.0 with HCl.

After mixing, the formoterol concentration of the formulation to beadministered is about 1.1 mg/ml.

Example 2

5 mg of formoterol (particle size: 5 :m) are metered as a suspensionwith 0.015 ml of a 20% by weight aqueous NaCl solution into the chamber(17). The pH is adjusted to 5.0 using HCl.

4.5 ml of a 1:1 water/ethanol (v/v) solution are placed in container(2). The solution contains 0.45 mg benzalkonium chloride and 2.25 mgNa-EDTA and is adjusted to a pH value of 5.0 with HCl.

Cartridges containing formoterol as active substance are preparedanalogously, the content of formoterol preferably being between 100 and400 mg/ml, most preferably between 250 and 350 mg/ml.

Example 3

In the container (2), 0.1% by weight of tiotropium bromide, 0.01% byweight of benzalkonium chloride and 0.05% by weight of EDTA areformulated in 4.5 ml of water as solvent. The pH is adjusted to 3.0using hydrochloric acid. The chamber (17) contains a 10 mg tabletconsisting of 0.5 mg of the buffer substance Na₂HPO₄×2 H₂O and 9.5 mg ofNaCl. When the cartridge is inserted in the inhaler, the buffersubstance from the chamber (17) is mixed with the solution in thecontainer (2) and a pH of 3.5 is thus achieved.

Analogously, cartridges are prepared with tiotropium bromide as activesubstance, wherein the content of tiotropium bromide is preferablybetween 0.002 and 0.4% by weight, most preferably between 0.0005 and 0.2by weight. The pH of the solution in the container (2), before mixingwith the buffer in the chamber (17), is preferably below 4.0 in thesecases, most preferably between 2.0 and 3.0 and particularly between 2.5and 3.0.

1. An apparatus comprising: a closure-cap and a container in the form ofa cartridge for separate storage of an active ingredient and apharmacologically acceptable liquid, wherein the closure-cap has: (i) aguide tube for passage of a capillary or canula through the closure-cap,(ii) a connecting piece which at least partially enters the containerthrough an upper edge of the container's neck when the closure-cap ispushed onto the neck, (iii) a chamber integral within the connectingpiece and including at least one opening, and (iv) a plunger disposeddownward from the upper edge of the neck within the chamber and sealingthe at least one opening thereof, the plunger including at least threesides defining a hollow space to hold one of the active ingredient andthe pharmacologically acceptable liquid, and at least one aperture thatis sealed when the plunger is in a first position and that opens whenthe plunger is in a second position.
 2. An apparatus according to claim1, wherein a penetrable septum is located in the closure-cap between theplunger and an upper extremity of the closure cap.
 3. An apparatusaccording to claim 1, wherein a penetrable septum or an elastic O-ringseal is formed in the guide tube.
 4. An apparatus according to claim 1,wherein the chamber has a further opening which is sealed by apenetrable, tearable or movable separating element.
 5. An apparatusaccording to claim 4, wherein the separating element is formed as asealing foil that also seals the at least one aperture of the plungerwhen it is in the first position.
 6. An apparatus according to claim 1,wherein the chamber has two or more compartments which are arranged oneabove the other and are each sealed from the other by a penetrable,tearable or movable separating element.
 7. An apparatus according toclaim 1, wherein the plunger has the shape of a cylinder with a ratio oflength to diameter of 1.2 to 2.0.
 8. An apparatus according to claim 1,wherein the at least one aperture opens on one side of the plungerfacing a wall of the chamber.
 9. An apparatus according to claim 8,wherein the wall seals the hollow space when the plunger is in the firstposition.
 10. An apparatus according to claim 8, wherein the hollowspace is sealed by a separating element.
 11. An apparatus according toclaim 1, wherein the hollow space is divided by at least one partitionwall into two or more compartments which are sealed from one another,and each compartment is sealed by a separating element or by a wall ofthe chamber.
 12. An apparatus according to claim 1, wherein a recess isformed in the plunger opening toward a head of the closure-cap.
 13. Anapparatus according to claim 1, wherein the plunger or at least one wallof the chamber is coated with a pharmacologically acceptable lubricant.14. An apparatus according to claim 13, wherein the pharmacologicallyacceptable lubricant is selected from the group consisting of oleicacid, lecithin and a sorbitan ester.
 15. An apparatus according to claim1, wherein the at least one aperture of the plunger opens toward theneck of the container.
 16. An apparatus according to claim 15, whereinthe at least one aperture of the plunger leading to the hollow space issealed by one or more projections formed on the connecting piece whenthe plunger is in the first position.
 17. An apparatus according toclaim 1, wherein the at least one aperture of the plunger leading to thehollow space is sealed by one or more projections formed on theconnecting piece when the plunger is in the first position.
 18. Anapparatus according to claim 1, wherein the plunger is up to 5% widerthan the opening which it closes.
 19. An apparatus according to claim 1,wherein the chamber contains a pharmaceutical concentrate in the form ofa suspension or a solution in a pharmacologically acceptablepropellant-free liquid with one or more active substances, the activesubstance or substances being suitable in particular for inhalativetherapy.
 20. An apparatus according to claim 19, wherein thepharmacologically acceptable propellant-free liquid is water, an aqueoussolution with pharmacologically acceptable salt, ethanol or a mixturethereof.
 21. An apparatus according to claim 19, wherein the activesubstance is selected from the group of betamimetics, anticholinergics,antiallergics, leukotriene antagonists, steroids and a mixture thereof.22. An apparatus according to claim 21, wherein the active substance isselected from formoterol, tiotropium, salbutamol, a salt thereof and amixture thereof.
 23. An apparatus according to claim 22, wherein thechamber contains a suspension of formoterol in a concentration ofbetween about 75 mg/ml and about 500 mg/ml.
 24. An apparatus accordingto claim 19, wherein the concentration of the active substances isbetween about 75 mg/ml and about 1000 mg/ml.
 25. An apparatus accordingto claim 24, wherein the concentration of the active substance isbetween about 75 mg/ml and about 500 mg/ml.
 26. An apparatus accordingto claim 25, wherein the concentration of the active substance isbetween about 100 mg/ml and about 400 mg/ml.
 27. An apparatus accordingto claim 19, wherein the container contains a solution of tiotropiumbromide in an amount of between about 0.0002 and about 0.4% by weight,and having a pH of from about 2.0 to about 4.0.
 28. An apparatusaccording to claim 27, wherein the container contains a solution oftiotropium bromide in an amount of between about 0.0005 and about 0.2%by weight.
 29. An apparatus according to claim 27, wherein the containercontains a solution of tiotropium bormide in an amount of about 0.1% byweight.
 30. An apparatus according to claim 1, wherein the activesubstance concentrate in the chamber contains an acid, a preservative, acomplexing agent, or a mixture of such elements.
 31. An apparatusaccording to claim 1, wherein the container contains a pharmacologicallyacceptable propellant-free liquid, which optionally contains an acid, acomplexing agent, a preservative, a surfactant, a buffer or a mixture ofsuch elements.
 32. An apparatus according to claim 31, wherein thesolvent or suspension agent contains one or more medicaments selectedfrom the group of betamimetics, anticholinergics, antiallergies,leukotriene antagonists, steroids and a mixture thereof.
 33. Anapparatus according to claim 31, wherein the chamber contains a buffersubstance.
 34. An apparatus according claim 1, wherein the cartridge isoperable for use with an atomizer.
 35. An apparatus comprising: acontainer having a neck leading to a volume for storing one of an activeingredient and a pharmacologically acceptable liquid; a closure capincluding: (i) a connecting piece which at least partially enters thevolume through the neck when the closure-cap engages the container, (ii)a chamber integral within the connecting piece and including at leastone opening at a lower end thereof, and (iii) a guide tube extendingthrough the closure cap to an upper end of the chamber; a plungerdisposed downward from the neck and sealing an upper end of the chamberwhen in a first position, the plunger being movable by inserting adevice through the guide tube; and a separating element sealing theopening at the lower end of the chamber, wherein movement of the plungerfrom the first position to a second position toward the lower end of thechamber breaks the seal by the separating element and permits the otherof the active ingredient and the pharmacologically acceptable liquid toexit the chamber and enter the volume of the container.
 36. An apparatusaccording to claim 35, wherein the plunger, chamber and separatingelement are adapted such that movement of the plunger toward the secondposition increases pressure within the chamber that causes the sealformed by the separating element to break.
 37. An apparatus according toclaim 36, wherein the separating element is formed from at least one ofa sealing foil and a stopper.
 38. An apparatus according to claim 36,wherein the separating element includes one or more frangible pointsthat assist in breaking the seal under pressure.
 39. An apparatusaccording to claim 36, wherein a side of the plunger facing theseparating element at least one of slops, tapers to a point, has one ormore spikes, and has one or more or cutting edges that assist inbreaking the seal.
 40. An apparatus according to claim 35, to whereinthe plunger, chamber and separating element are adapted such that theplunger engages the separating element as the plunger moves toward thesecond position that causes the seal formed by the separating element tobreak.
 41. An apparatus according to claim 40, wherein the separatingelement includes one or more frangible points that assist in breakingthe seal under pressure.
 42. An apparatus according to claim 40, whereinthe separating element is formed from a sealing foil.
 43. An apparatusaccording to claim 42, wherein a side of the plunger facing theseparating element at least one of slops, tapers to a point, has one ormore spikes, and has one or more or cutting edges that assist inbreaking the seal.
 44. An apparatus comprising: a container having aneck leading to a volume for storing one of an active ingredient and apharmacologically acceptable liquid; a closure cap including: (i) aconnecting piece which at least partially enters the volume through theneck when the closure-cap engages the container, (ii) a chamber integralwithin the connecting piece and including at least one opening at alower end thereof, and (iii) a guide tube extending through the closurecap to an upper end of the chamber; and a flexible plunger disposeddownward from the neck and sealing an upper end of the chamber when in afirst position, the plunger having a first surface communicating withthe guide tube such that a cannula may engage the first surface throughthe guide tube, wherein the plunger is operable to deform in response toforce applied by the cannula such that frictional forces between theplunger and walls of the chamber are reduced.
 45. The apparatus of claim44, wherein the deformation of the plunger in response to the forceapplied by the cannula reduces canting within the chamber.
 46. Theapparatus of claim 44, wherein: the plunger includes a substantiallyplanar second surface oppositely facing from the first surface; and thedeformation of the plunger in response to the force applied by thecannula causes the second surface to become non-planar.
 47. Theapparatus of claim 46, wherein the second surface becomes substantiallytapered in cross-section in response to the deformation of the plunger.48. The apparatus of claim 47, wherein the second surface becomessubstantially V-shaped in cross-section in response to the deformationof the plunger.
 49. The apparatus of claim 46, wherein the plungerincludes a cup-shaped portion having an opening and an interior volume,the first surface being disposed away from the opening within theinterior volume.
 50. The apparatus of claim 49, wherein the opening andthe first surface include dimensions transverse to the direction of theguide tube that are greater than a diameter of the cannula.
 51. Theapparatus of claim 49, wherein the interior volume and the first surfaceare substantially centrally located within the plunger.
 52. Theapparatus of claim 44, wherein movement of the plunger from the firstposition to a second position toward the lower end of the chamberpermits the other of the active ingredient and the pharmacologicallyacceptable liquid to exit the chamber and enter the volume of thecontainer.